Many critics of the pharmaceutical industry are of the view that there is a shortage of effective medications for many chronic neurologic conditions. These conditions may include traumatic brain injury (TBI), stroke, multiple sclerosis (MS), schizophrenia, autism, insomnia, post-traumatic stress disorder (PTSD), dementia and Alzheimer's disease (Alzheimer's), Parkinson's disease (Parkinson's) and numerous other neurological conditions and disorders. Some are of the view that the available medications for psychiatry are either no better than placebos or could even be harmful. As a result, many patients with neurological conditions seek alternative therapies.
One field of alternative therapy, brain stimulation techniques, have been used some time, based on the fact that the neural system has responded to these techniques in substantive ways. Many of these techniques are based on electrical and magnetic impulses. The following listing constitutes the major methods currently used to stimulate the human brain for therapeutic purposes.
1. Electroconvulsive Therapy (ECT)
Electroconvulsive therapy (ECT) is one of the oldest methods used to electrically induce seizure in anesthetized patients in order to treat difficult cases of severe depression, mania and catatonia (see for example, Rudorfer, M V, Henry, M E, Sackeim, H A (2003). “Electroconvulsive therapy”. In Tasman A, Kay J, Lieberman J A (eds) Psychiatry, Second Edition. Chichester: John Wiley & Sons Ltd, 1865-1901). The mechanism of action of the ECT method is not fully understood, and there is no general consensus on the treatment protocol. Furthermore, the ECT method carries the risk of damaging the brain, such injury being represented by cognitive deficits (see for example, Breggin P (2007). “ECT Damages the Brain: Disturbing News for Patients and Shock Doctors Alike”. Ethical Human Psychology and Psychiatry. 9(2): 83-86). In addition, the consequent loss in IQ and memory from the therapy is also significant (see Andre L (2009). “Doctors of Deception: What They Don't Want You to Know About Shock Treatment”. Rutgers University Press).
2. Cranial Electrotherapy Stimulation (CES)
Another electrical brain stimulation technique involves cranial electrotherapy stimulation (“CES”). The CES method applies a small pulsed electric current across the patient's head. Some medical practitioners claim that CES helps with conditions such as stress, anxiety, depression and insomnia. However, it is still an experimental technique (see for example, Klawansky S (1995). “Meta-Analysis of Randomized Controlled Trials of Cranial Electrostimulation: Efficacy in Treating Selected Psychological and Physiological Constitutions”. Journal of Nervous & Mental Disease 183(7):478-484). The proposed mechanism of action for CES is that the pulses of electric current increase the ability of the neural cells to produce serotonin, dopamine, DHEA, endorphins and other neurotransmitters that stabilize the neurohormonal systems (see Gilula M F, Kirsch D L (2005). “Cranial Electrotherapy Stimulation Review: A Safer Alternative to Psychopharmaceuticals in the Treatment of Depression”. Journal of Neurotherapy. 9(2)). Some believe that CES may help relieve certain stress-related symptoms but it has not been studied sufficiently to determine whether its use is practical and cost-effective (see Barrett S (2008). “Dubious Claims Made for NutriPax and Cranial Electrotherapy Stimulation”. QuackWatch online, accessed on May 2012).
3. Deep Brain Stimulation (DBS)
Deep brain stimulation (DBS) utilizes implants which function by delivering measured doses of electrical stimulation via a thin electrode surgically inserted through a small hole in a patient's skull, with its tip implanted in a targeted brain area. The U.S. Food and Drug Administration (FDA) approved DBS devices and procedures for treatment of a disorder called “essential tremor” in 1997; for treatment of Parkinson's disease in 2002; and for treatment of dystonia in 2003 (see Kringelbach M L, Jenkinson N, Owen S L F, Aziz T Z (2007). “Translational principles of deep brain stimulation”. Nature Reviews Neuroscience. 8:623-635). More recently, Alzheimer's Disease reportedly also responds to DBS (see Wood J (2012). “Brain Pacemaker Shows Promise in Fighting Alzheimer's Disease”. PSychCentral.com online (May 12, 2012)). Despite their success, DBS treatments can be overactive in its effects, leading to an outcome which can trigger dizziness, tingling, and other undesirable side effects. Researchers also still do not understand how DBS treatment actually works in-vivo.
4. Transcranial Light Therapy (TLT)
Transcranial light therapy (“TLT”) or transcranial photobiomodulation (“tPBM”) is enjoying attention in recent years due to sound scientific principles, successful outcomes, lack of side-effects and being non-invasive. This method involves directing light to the brain through the outside of the skull. The source of light can be light emitting diodes (LED) or a low level laser source, usually in the red or near infrared-red (NIR) part of the spectrum. The NIR band would be the preferred choice in order to provide deeper penetration through the meninges, cranial material and then through the brain matter, in order to reach the deeper parts of the brain. Recent research supports transcranial light therapy's potential for treating stroke, traumatic brain injury, Parkinson's disease, mild cognitive impairment, Alzheimer's disease, depression, and some other cognitive issues (see for example, Rojas J C, Gonzalez-Lima F (2011). “Low-level light therapy of the eye and brain”. Eye and Brain. 3:49-67). More recently, it has also been found that this modality can also enhance cortical metabolic capacity and retention of extinction memories, reduce fear renewal, and implicate low level light therapy as a novel intervention to improve memory (Rojas J C et al (2012). “Low-level light therapy improves cortical metabolic capacity and memory retention”. J Alzheimer's Dis. 2012; 32(3):741-52).
5. Ear Canal Transcranial Light Therapy
Ear canal transcranial light therapy was developed following a study in Finland that demonstrated that when bright light is directed into the ears, it helps to treat seasonal affective disorder (SAD) or winter depression (Timonen M et al (2012). “Can transcranial brain-targeted bright light treatment via ear canals be effective in relieving symptoms in seasonal affective disorder?” Medical Hypothesis. 78(4):511-515). The commercially sold device has diodes in the form of ear buds with very bright white LED attached by cables to a controller unit. It is consumer-friendly and appears effective for SAD.
6. Optogenetic Neurostimulation
In the optogenetic neurostimulation (optogenetics) process, researchers first introduce a gene for a light-sensitive molecule, called channelrhodopsin 2 (ChR2), into a specific subset of neurons. Shining blue light on these neurons then causes them to fire. One advantage of this approach is its specificity, i.e., only the neurons with the gene are activated. This process also provides a way to shut neurons off, by introducing a different molecule, halorhodopsin (“NpHR”), which uses the energy of yellow light to silence the cells. The combination of these elements makes the technique very exact in achieving specific neuro-outcomes. Research with optogenetics can lead to important understandings in relating anatomical locations of the brain with predictable behavioral outcomes. The exactness of how behavior can be manipulated has great appeal in advancing neuroscience. However, at this time, the challenge is to translate animal experiments to human applications. The technique is still very much in the laboratory domain, involving small animals (mainly rats and mice). It is an invasive method involving implanting a light probe inserted into the brain, and connecting from the targeted brain area to a controller unit via a catheter holding an optic fiber. To achieve precise stimulatory outcomes, it also requires the introduction of ChR2 into the specific areas of the brain to have the desired neurons fire. The precision of the optogenetics method is highly appealing to scientists, but it is expected to stay in the research laboratory domain for the foreseeable future. Today, over 500 laboratories are applying optogenetic tools to animal models of Parkinson's, blindness, spinal injury, depression, narcolepsy, addiction, and memory (see Williams M (2010). “A brain implant that uses light”. Technology Review online article published on Feb. 24, 2010).
7. Intranasal Light Therapy
Intranasal light therapy involves directing light energy through the nasal cavity and into the brain. Researchers have found that Intranasal Light Therapy provides positive outcomes with neurologic conditions such as insomnia, mild cognitive impairment, Alzheimer's disease, Parkinson's disease, schizophrenia, migraine and headaches, and stroke (cerebral infarction) in humans.
Summary of Current Brain Stimulation Techniques:
There is good data supporting the efficacy of all these conventionally known methods, thereby confirming that the brain responds to light, and brings about therapeutic outcomes in various forms. However, they are all very different ways of stimulating the brain for therapeutic purposes. Most treatment methods are either deployed in laboratory conditions on animals; or if deployed on human beings, largely have to be administered under clinical supervision. The optogenetics method understandably has attracted a great amount of attention in neuroscience circles because of the exactness in which it can extract neural outcomes through precise anatomical manipulation of the brain. However, the invasiveness and set-up required keeps it in the laboratory domain. One conventional method to date that has significant potential to become a consumer-friendly product, the ear canal transcranial method, is employed solely and specifically for treating seasonal affective disorder.
The methodology that seems to have great potential to treat a wide range of medical conditions is the transcranial method. For over a decade, transcranial photobiomodulation (PBM) has produced positive effects in laboratory animals and human subjects. Animal studies included acute traumatic brain injury (TBI), Alzheimer's, depression and stroke, while human studies, included TBI, depression and stroke. Furthermore, low level light energy has been found to be safe for humans in the stroke studies, without the side effects often associated with medications.
However, transcranial devices have yet to be developed to the point where they are portable and mass produced at a low cost. Instead, such devices are mainly available only in research labs because they are expensive to manufacture, have power requirements that do not allow them to be portable, and require training to use. Furthermore, such transcranial devices are designed such that the light energy is unlikely to reach important primal regions that are located on the underside of the brain. Amongst other functions, these primal regions govern memory, behavior and emotions.
Intranasal light therapy can be used to reach some of these regions located on the underside of the brain because they are closer to the nasal region than the scalp. Delivering light energy through the nasal cavity has the additional advantage in that the subject's scalp or hair do not act as barriers. However, light energy from an intranasal source are less likely to reach areas of the brain distal from the nasal cavity, such as the dorsal cortical areas around the top of the head.
Scientific Basis and Evidence for Brain Irradiation Therapy:
Because of the ineffectiveness of drugs in addressing many neurological disorders, increasing attention is being directed to alternative treatments, such as light therapy. Various research studies clearly show and factually evidence a variety of beneficial in-vivo effects of low-level light therapy (LLLT) on the brain. In animal research studies, low-level light therapy has been found to be promising for treating anoxic brain injury, atherothrombotic stroke, embolic stroke, Parkinson's Disease, mild cognitive impairment and Alzheimer's Disease. Similarly, in human studies, low-level light therapy has been found to be promising for improving on the effects of ischemic stroke, traumatic brain injury, depression and functions of the prefrontal cortex.
Mechanism of Action for Brain Irradiation Therapy:
FIG. 17 shows one intracellular mechanism of low level light therapy. As illustrated, one key to the therapeutic response of the brain lies in the presence of a photoacceptor respiratory enzyme which exists in all cellular mitochondria, cytochrome oxidase. The cytochrome oxidase enzyme represents the best known intraneural marker of metabolic activity; and its enzyme activity is tightly coupled with free radical metabolism, cell death pathway, and glutamatergic (a neurotransmitter related) activation, important for learning and memory (see for example, Wong-Riley M T (1989). “Cytochrome oxidase: an endogenous metabolic marker for neural activity”. Trends Neurosc. 12(3):94-101).
Photoacceptors, unlike photoreceptors found inside the eyes, do not process light energy, but are instead a component part of the normal metabolic pathways. Photoacceptors are sensitive to light in the visible red region and near-infrared region of the light spectrum, and are able to convert the absorbed light of these red and near-infrared wavelengths into cellular energy molecules of adenosine triphosphate (ATP). When light of these visible red and near-infrared wavelengths (at low energy levels) enter living cells (including nerve cells), the light energy modulates the cell's activity of metabolism (photobiomodulation) by regulating internal mitochondrial function, the intraneuronal signaling systems, and the redox states. Moreover, empirical experiments show that photoneurobiomodulation of electrical activity in neurons can be achieved independently of thermal effects (see Fork R L (1971). “Laser stimulation of nerve cells in Aplysia”. Science. 171(974):907-908). Also, when employed and delivered at low energy levels, the therapeutic effects of brain-absorbed light energy are not accompanied by any substantive complications or major side effects. Thus, with the neurons of the brain affecting virtually all functions and activities of the living body, the impact of exposing the brain to modulating light energy consequently affects the entire medical condition of the human being.
At the cellular level, the sensitivity of cytochrome oxidase to red light and near infrared red light may be explained by the role of the chromophore in the protein structure. The chromophore is an organic structural entity that is present in all photoreceptors, such as those present in the eyes and which give us the perception of colors. These chromophores will absorb only particular light wavelengths and reject all others; and the cytochrome oxidase in the chromophores are known to accept red and near-infrared red light energy.
These underlying facts accurately identify the potential impact of light energy irradiation that could be purposely directed into one or more anatomic parts of the living brain on-demand, resulting in both beneficial therapy for and prophylaxis against a variety of medically recognized nervous disorders and pathological states.
Photoacceptors in the Nervous System:
Although earlier-reported animal experiments suggested the presence of photoacceptors in the brain, it was only those particular experiments and empirical results first reported in 2000 which correctly demonstrated that isolated mitochondria are sensitive to irradiation with monochromatic light in the red and near-infrared red regions of the light spectrum. Thus, it was empirically demonstrated that illumination of isolated rat liver mitochondria with red low-powered lasers increased ATP synthesis and oxygen consumption (Karu T (2000). “Mechanism of low-power laser light action on cellular level”. Proc SPIE. 2000; 4159:1-17). In addition, it has been empirically demonstrated that impaired mitochondrial oxidative metabolism is associated with neurodegeneration (see Wong-Riley M T et al (2001). “Light emitting diode treatment reverses the effect of TTX on cytochrome oxidase in neurons”. Neuroreport. 12(14):3033-3037). Also, research studies revealed that rat neuronal cultures exposed to low level red light showed increases in cytochrome oxidase activity (see Wong-Riley M T et al (2005). “Photobiomodulation directly benefits primary neurons functionally inactivated by toxins: role of cytochrome c oxidase”. J Biol Chem. 280(6):4761-4771).
Accordingly, a light-modulating method, system and apparatus aimed at improving mitochondrial metabolism in-vivo would be of major benefit to the functionality of both the diseased and normal brain tissues. Such a light-modulating methodology is also believed to potentially relieve pain in humans (see Chow R t et al (2009). “Efficacy of low-level laser therapy in the management of neck pain: a systematic review and meta-analysis of randomised placebo or active treatment controlled trials”. Lancet. 374(9705):1897-1908).
It is also noteworthy that the effects of light irradiation on the brain are observed to be effective in a wavelength-specific range. The primary photoacceptor mediating the effects of the light is not only localized to the mitochondria; the molecules that absorb the light in cells are believed to be part of the respiratory chain (see Karu T (1989). “Laser biostimulation: a photobiological phenomenon”. J Photochem Photobiol B. 3(4):638-640).
Equilibrium and Homeostasis:
It is recognized that there comes a point when the photoacceptors (such as cytochrome oxidase) do not respond to further photostimulation. This critical event occurs when the photoacceptors are fully reduced or fully oxidized by the absorbed light energy; thus, photoacceptors can respond to light energy exposure only when they are in their intermediate stage (see Karu T I, et al (2008). “Absorption measurements of cell monolayers relevant to mechanisms of laser phototherapy: reduction or oxidation of cytochrome c oxidase under laser radiation at 632.8 nm”. Photomed Laser Surg. 26(6):593-599). Accordingly, when the photoacceptors become fully reduced or are fully oxidized, further sequential low power irradiation will not yield further metabolic activity from the photoacceptors. This indicates that the living cells in the body have coded action potential limits when they are ex-homeostasis; and thus, the neurons of the brain have the potential to respond positively to light irradiation only until they reach a state of homeostasis.
Neural Conditions Suitable for Light Irradiation Treatment:
There are many potential neural conditions that can benefit from light irradiation of one or more regions of the brain in-vivo. Some of these medical conditions are summarily described below. In addition, it will be noted and appreciated that a wide range of other neural diseases, disorders, and pathological states are also envisioned to be effectively therapeutically treatable using the present invention. Examples of these other neural conditions are expected to include, but not limited to epilepsy, migraine, chronic fatigue syndrome, encephalitis, multiple sclerosis, anxiety disorder, attention deficit disorder, schizophrenia, and learning disabilities.
1. Treatment of Stroke, Neurotrauma, Cognition and an Emotional Mind State
Human and animal studies that relate to treatment of stroke, neurotrauma, cognition, emotional states, and similar neurological disorders are well documented (see for example, Rojas J C, Gonzalez-Lima F. “Low level light therapy of the eye and brain”. Eye and Brain. 2011; 3:49-67). The brain, being the neurological control center of systemic body health, has a direct impact on all body health. For example, the health of the hypothalamus, being the key regulating gland for systemic homeostasis, has a profound impact on overall body health; and thus, a functionally improved hypothalamus will concomitantly yield a greater degree of systemic homeostasis. Also, research studies have extensively investigated brain irradiation for both stroke and neurotrauma. For example, recent studies by Uozemi et al. have demonstrated that low energy light delivered transcranially was able to increase blood flow by 30% (Uozumi Y et al (2010). “Targeted increase in cerebral blood flow by transcranial near-infrared laser irradiation”. Lasers SurgMed. 42(6):566-576). Such demonstrated beneficial results with light irradiation have been accompanied with significant increases in nitric oxide production, a mechanism that is associated with the relaxation of vascular walls to achieve improved blood circulation. Thus, the cerebral blood flow was shown to be increased in both treated and untreated hemispheres. Also, subjects pretreated with light irradiation showed improved blood flow during the period of occlusion, with stable body temperature, heart rate and respiratory rates. The overall result is a significant decrease in apoptotic cells during a stroke event.
Regular irradiation with low level near infrared red (NIR) light has also been found to be associated with significant neurological recovery after stroke events (see Detaboada L et al (2006). “Transcranial application of low-energy laser irradiation improves neurological deficits in rats following acute stroke”. Lasers Surg Med. 38(1):70-73). Furthermore, these recovery effects were associated with increased neuronal proliferation and migration in the subventricular zone, which plays a role in neurogenesis (see Oron et al (2006). “Low-level laser therapy applied transcranially to rats after induction of stroke significantly reduces long-term neurological deficits”. Stroke. 37(10):2620-2624; see also Lampl Y et al (2007). “Infrared laser therapy for ischemic stroke: a new treatment strategy: results of the NeuroThera Effectiveness and Safety Trial-1(NEST-1)”. Stroke. 38(6):1843-1849).
2. Treatment of Traumatic Brain Injury
Published research studies have provided in-vivo evidence that the effects of low level light irradiation on cytochrome oxidase and the release of nitric oxide plays a major role in the neuroprotective action of light irradiation therapy not just against ischemia, but also against traumatic brain injury (see Naeser M A et al (2010). “Improved cognitive function after transcranial, light-emitting diode treatments in chronic, traumatic brain injury: two case reports”. Photomed Laser Sur. 29(5):351-358).
3. Treatment of Neurodegenerative Diseases
Light irradiation of the brain has been found to support neurogeneration in-vivo. Thus, light energy irradiation can therapeutically treat a range of different neurodegenerative diseases and disorders, such as Parkinson's disease which is specific to the substantia nigra, a part of the mid-brain area located behind the hypothalamus; and which can be reached with NIR light wavelengths. In a study using small animals like mice, it was demonstrated that low level light irradiation at 670 nm wavelength helps prevent the loss of dopaminergic cells in the substantia nigra (see Shaw V E et al (2010). “Neuroprotection of midbrain dopaminergic cells in MPTP-treated mice after near-infrared light treatment”. J Comp Neurol. 518(1):25-40). However, longer wavelengths of light energy (such as near-infrared light (NIR)) are considered to be more feasible for much larger mammalian subjects such as a human being.
4. Treatment of Depression and Similar Emotional Deficits
Phenotypic expressions of mood disorders such as depression and post-traumatic stress disorder (PTSD) have been shown to be associated with decreased metabolic capacity in the prefrontal cortex region (see Shumake J, Gonzalez-Lima F (2003). “Brain systems underlying susceptibility to helplessness and depression”. Behav Cogn Neurosci Rev. 2(3):198-221). Electrical stimulation of the prefrontal cortex has been shown to have antidepressant effects (Hamani C et al (2010). “Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats”. Biol Psychiatry. 67(2):117-124). Thus, light irradiation of the prefrontal cortex region with red light and near-infrared red light may cause an increase of metabolic capacity in the prefrontal cortex region, as well as provide potential neuroprotection against these medical conditions. Indeed, a pilot study showed that when the foreheads of human patients suffering from major depression and anxiety were irradiated with low level light of 810 nm wavelength, the blood flow to the frontal cortex increased and induced a 63% reduction in depression scores (see Schiffer F (2009). “Psychological benefits 2 and 4 weeks after a single treatment with near infrared light to the forehead: a pilot study of 10 patients with major depression and anxiety”. Behav Brain Funct. 5:46).
5. Treatment of Memory Deficits
Research studies have demonstrated that irradiation of the prefrontal cortex region of the brain with near-infrared red light of 1072 nm wavelength improved an individual's functional memory (see Mikhalikova S et al (2008). “Emotional responses and memory performance of middle-age CD1 mice in a 3D maze: effects of low infrared light”. Neurobiol Learn Mem. 89(4):480-488). As this memory deficit condition is common among the more elderly, using light irradiation methods to treat the prefrontal cortex region of the brain can help with the aging-related problem of working memory deficits.
6. Treatment of Dementia and Alzheimer's Disease
Neurodegeneration can lead to cognitive impairment that is often medically identified with dementia. Causing an improved blood flow has therapeutic potential for addressing and treating vascular dementia. Alzheimer's disease, although medically a form of dementia, apparently has a variety of different causes. The early signs/symptoms of this neurodegenerative condition are typically revealed as regional brain metabolic deficits in the form of reduced cytochrome oxidase activity, an overt sign for potential risk of Alzheimer's disease (see Valla J et al (2001). “Energy hypometabolism in posterior cingulated cortex of Alzheimer's patients: superficial laminar cytochrome oxidase associated with disease duration”. J Neurosci. 21(13):4923-4930). Because brain irradiation with red and infrared red light energy demonstrably activates cytochrome oxidase, a light irradiation treatment procedure can help manage the symptomatic onset of a full Alzheimer's disease state.
Animal studies demonstrate that the delivery of near infrared (NIR) light energy could improve the condition of a cognitive impaired brain associated with Alzheimer's disease (AD). Studies have found that low level light therapy (LLLT) improves cortical metabolic capacity and memory retention in mice. It is believed that the ability of LLLT to increase mitochondrial energy metabolism could be utilized to recover brain processes impacted by regional brain hypometabolism associated with AD (see Rojas J C, Bruchey A K and Gonzalez-Lima F (2012). Low-level Light Therapy Improves Cortical Metabolic Capacity and Memory Retention. Jnl. Alzheimer's Disease. 32(3): 741-52).
A further study using two transgenic mouse models suggests that NIR light may have the potential as an effective, minimally-invasive intervention for mitigating, and even reversing, progressive cerebral degenerations associated with dementia and AD. Their results suggest that significant reversal of AD pathology has been induced by NIR treatment (see Porushothuman S, Johnstone D M, Nandasena C, Mitrofinas J and Stone J (2014). Photobiomodulation with near infrared light mitigates Alzheimer's disease-related pathology in cerebral cortex, evidence from two transgenic mouse models. Alzheimer's Research & Therapy. 6:2).
It has also been proposed that LLLT that can be directed to proliferate mesenchymal stem cells (MSC). This can ameliorate the progression of AD as demonstrated in a mouse model (see Farfara D, Tuby H, Trudler D, Doron-Mandel E, Maltz L, Vassar R J, Frenkel D and Oron U (2015). Low-level Laser Therapy Ameliorates Disease Progression in a Mouse Model of Alzheimer's Disease. J Mol Neurosc. 55: 430-436).
Further, it has been proposed that intranasal light therapy can enhance the activity of the SIRT1 enzyme activity (see Liu T C Y, Wu D E, Gu Z Q and Wu M (2010). Applications of Intranasal Low Intensity Laser Therapy in Sports Medicine. Jnl. Innovative Optical Health Sc. 3(1): 1-16), and this activity helps in the differentiation of mesenchymal stem cells (see Joe I S, Jong S G and Cho G W (2015) Resveratrol-induced SIRT1 activation promotes neuronal differentiation of human bone marrow mesenchymal stem cells. Neurosci Lett. January 1; 584: 97-102).
The histological activities underlying the reaction of AD and demented brains to LLLT can be explained by the observations of several published investigations. In 2002, it was demonstrated that weak light could be used to guide the direction taken by the leading edge or growth cones of a nerve cell. In actively extended growth cones, a laser spot is placed in front of a specific area of a nerve's leading edge, enhancing growth into the beam focus and resulting in guided neuronal turns as well as enhanced growth (see Erlicher A, Betz T, Stuhtmann, Koch D, Milner V and Raizen J (2002). Guiding neuronal growth with light. PNAS 99(22): 16024-16028). This phenomenon was repeated in another experiment in 2013 (see Black B, Mondal A, Kim Y and Mohanty S K (2013). Neuronal Beacon. Optical Society of America Optics Letter. 38(13): 2174-2176). Nerve cells appear to have an innate attraction to low energy light forces.
Researchers have also found that cells repair themselves when exposed to red low level light, as seen in FIG. 18. FIG. 18 shows a neurite elongation experiment with in vitro post-oxidative stress (670 nm, 3 mW, 20 sec/day, 5 days). Neurites of neurons that were shortened by oxidative stress would re-elongate. The data suggest that red light irradiation protects the viability of cells in the case of oxidative stress. It also stimulates neurite outgrowth (see Giuliani A, Lorenzini L, Gallamini M, Masella A, Giardino L and Calza L (2009). Low infrared laser light irradiation on cultured neural cells: effects on mitochondria and cell viability after oxidative stress. BMC Com Alt Med. 9:8). As such, there is a basis to believe that if low level red and NIR light energy can be delivered to neurons that are functioning sub-optimally, a healing response is possible.
The Default Mode Network (DMN):
The Default Mode Network (DMN) of the brain has attracted interest because it has been associated with Alzheimer's disease, dementia, autism, schizophrenia, depression, chronic pain, Parkinson's disease, multiple sclerosis (MS) and post-traumatic stress disorder (PTSD). The DMN is active when individuals are engaged in internally focused tasks including memory retrieval, envisioning the future, and conceiving the perspective of others (see Buckner R L, Andrews-Hanna J R and Schacter D L (2008). The Brain's Default Network: Anatomy, Function, and Relevance to Disease. Ann. N.Y. Acad. Sci. 1124:1-38).
Regarding brain disorders, researchers have discovered targeted nexuses in the DMN, referred to as the “cortical hubs”. As shown in FIG. 19, the cortical hubs comprise: (i) the dorsal medial prefrontal cortex 502; (ii) the ventral medial prefrontal cortex 504; (iii) the hippocampus and entorhinal cortex 506; (iv) the precuneus 508; (v) the lateral parietal lobe 510; and (vi) the posterior cingulate cortex 512. These hubs are highly connected in the DMN, although some of them may lie outside the network. Buckner et al suggested that cortical hubs interconnect distinct, functionally specialized systems. Through positron emission tomography amyloid imaging these hubs showed high amyloid-β deposition in the locations consistent with the possibility that hubs, while acting as critical way stations for information processing, may also augment the pathological cascade in AD (Buckner R L, Sepulcre, Talukar T, Krienen F M, Liu H, Hedden T, Andrews-Hanna J R, Sperling R A and Johnson K A (2009). Cortical Hubs Revealed by Intrinsic Functional Connectivity: Mapping, Assessment of Stability, and Relation to Alzheimer's Disease. J. Neurosci. 29(6): 1860-1873).
Experiments have shown that Aβ deposition in Alzheimer's disease occurs preferentially in the locations of cortical hubs (see Stam C J (2014). Modern Network science of neurological disorders. Neuroscience 15:683).
Another important brain network may be the Salience Network (SN). Neurodegenerative illnesses such as Alzheimer's and Parkinson's target the DMN, whereas behavioral variant disorders such as frontotemporal dementia (FTD) target the more anterior-located SN. While the DMN is identified with the whole brain, the SN emphasizes the anterior of the brain which is anchored by the anterior insula and the anterior cingulate cortex. While it appears that the DMN and SN may be different from each other, they are connected to each other in many activities. The SN plays an important role in driving the switches between the DMN and the central executive networks. These networks are thought to be heavily involved in handling novel situations outside the domain of some of our ‘automatic’ psychological processes.
Neurological Disorders Associated with Lesions in Cortical Hubs:
It has been proposed that lesions in the cortical hubs are associated with the at least the following brain disorders: schizophrenia, Alzheimer's disease, frontotemporal dementia, Parkinson's disease, temporal lobe epilepsy, Gilles de la Tourette syndrome, acute brain injury (coma), and migraine. Ischemia and oxidative stress are identified with these lesions.
Photobiomodulation (PBM) can potentially stimulate these lesions in the cortical hubs to heal. As mentioned above, it has been shown that weak light attracts the leading edge of growth cones of a nerve cell. When a beam of light is positioned in front of a specific area of a nerve's leading edge, this draws its growth towards the direction of the light, as well as enhances its overall growth. Nerve cells appear to “feed” on low energy light. As shown in FIG. 18, researchers also found that cells repair themselves when they are exposed to low energy red light. The neurites of neurons that were shortened by oxidative stress would re-elongate. The data suggests that red light irradiation protects the viability of cells and stimulates neurite outgrowth in cases of oxidative stress. In the specific case of Alzheimer's-related lesions, transgenic mice with Alzheimer's recovered memory function and cognition function with transcranial PBM. An autopsy on the brains of these mice revealed a reduction of the lesions associated with the biomarkers, Aβ plaques and neurofibrillary tangles.